Heparin stent

ABSTRACT

There is provided a medical device adapted for insertion into a human or animal body, characterised in that its exterior surface is coated with (1) an inner first layer of a biocompatible carrier comprising a sulphated glycosaminoglycan and providing sustained release of a biologically active agent dissolved or dispersed therein; (2) an outer second layer consisting of a film of the biologically active agent applied on the inner first layer, where the film optionally may contain at least one non-polymeric adjuvant, diluent or carrier. The present medical device is especially well suited for treatment or prevention of restenosis and disorders related thereto, and the sulphated glycosaminoglycan provides improved biocompatibility.

FIELD OF THE INVENTION

The present invention relates to a medical device adapted for insertioninto a human or animal body as well as a method for use thereof inpromoting tissue healing and in treatment of restenosis and disordersrelated thereto.

BACKGROUND OF THE INVENTION

During the last years, local drug administration has become anincreasingly more attractive means of treatment of various disorders. Asis well known, local drug administration mainly offers both a reducedrisk of unwanted systemic side-effects and much less generalinconvenience for all parties involved. Hence, a vast number of variousmedical devices and methods providing direct application of drug(s) to adiseased site have been disclosed. Typical such medical devices andmethods are disclosed in U.S. Pat. No. 5,861,168, U.S. Pat. No.5,591,227, WO 96/35416, WO 99/08729 and EP 879 595, the teachings ofwhich are incorporated herein by reference.

Stenotic lesions of vasculature are common disorders which often lead toarterial occlusive disease. Indeed, the latter is the most frequentlyencountered problem of vascular disease, and particularly ofcardiovascular disease. In general, approximately 50% of the patientswith significant cardiovascular disease will be treated withpercutaneous coronary angioplasty, whereby a balloon angioplasty isusually performed. However, the high incidence of restenosis, reaching30-50% in several studies, following such ballon angioplasty continuesto restrict the long-term success of this procedure (Kastrati, A.,Schomig, A., Elezi, S., Schulen, H., Wilhelm, M., Dirschinger, J.,Circ., 97, 2396 (1998)).

In order to treat the aforementioned resulting restenosis, stentimplantation has lead to some success.

Various medical devices having a coating which provides local rapidrelease of nitric oxide (NO) have. been disclosed as a potentially moresuccessful alternative. Typical such medical devices are disclosed in WO96/35416 referred to above. This reference suggests many types ofmedical devices providing release of NO, such as i) a medical devicepartially or completely coated with a nitric oxide adduct either as thecoating per se or in a coating matrix, ii) a medical device lo partiallyor completely produced from a material which includes an NO adduct, andiii) a medical device derivatised with an NO adduct. As for coatedstents, WO 96/35416 explicitly discloses only a Palmaz-Schatz stentcoated with a layer of a bovine serum albumine (BSA) conjugate ofS-nitrosothiol (Example 5). All the other examples relate to coatedcatheters. Related teachings are disclosed in WO 99/08729, where aballoon catheter coated with a layer of molsidomine is utilised.

Here it should be mentioned that molsidomine is a nitric oxide donorwhich belongs to the substance group of sydnonimines. This type ofcompounds are known for their ability to release NO without need ofenzymatic catalysis (Lablanche, J-M. et al., Circ., 95(1), 83 (1997)).Diethylenetriamine/nitric oxide adduct (DETA/NO) is a similar NOreleasing compound. (Maragos C. M. et al. J. Med Chem. 34:3242-3247.(1991)

As for the aforementioned types of coated medical devices, two mainproblems are associated therewith. Firstly, the type of coating used isnot potent enough to promote tissue healing, particularly vascularhealing, to such an extent that beneficial long-term effects areattained. Accordingly, the hitherto known coatings are not potent enoughto treat restenosis in such a manner that it ceases to be detrimental tothe patient on a more long-term basis. Secondly, said type of coatingelicits virtually no prophylactic effect. Furthermore, there is ageneral need for improving the biocompatibility of the surfaces ofmedical devices adapted for insertion into living tissue.

There is of course a strong demand in the art to provide a medicaldevice which overcomes all-of the above disadvantages.

EP 879 595 discloses a medical device having a coating comprising aninternal reservoir layer and an outer layer, where the outer layercomprises an ionic surfactant complexed to a biologically activematerial. The internal reservoir layer comprises a polymer incorporatingthe biologically active material. However, the present invention doesnot utilise any such ionic surfactant complex formation.

U.S. Pat. No. 5,591,227 discloses stents coated with layers of polymerand fibrin incorporating a therapeutic substance. As set forth below,the content and design of those layers are substantially different fromthe present invention.

In summary, the characterising features of the medical device accordingto the present invention are neither disclosed nor suggested in any oneof the aforementioned references.

DISCLOSURE OF THE INVENTION

According to the present invention, there is provided a novel medicaldevice which overcomes the problems referred to above. Indeed, thefeatures of the present medical device provide a solution of theseproblems also for many other types of disorders (vide infra) in additionto vascular damage(s) and restenosis. Owing to a careful choice ofcomponents, excellent biocompatibility is also provided. Morespecifically, the present invention relates to a medical device adaptedfor insertion into a human or animal body, characterised in that itsexterior surface is coated with

-   -   i) an inner first layer of a biocompatible carrier comprising a        sulphated glycosaminoglycan and providing sustained release of a        biologically active agent dissolved or dispersed therein;    -   ii) an outer second layer consisting of a film of said        biologically active agent applied on said inner first layer,        where said film optionally may contain at least one        non-polymeric adjuvant, diluent or carrier.

As used herein, the expression “sulphated glycosaminoglycan” alsoencompasses molecules comprising a sulphated glycosaminoglycan moiety.Thus, said expression not only comprises the substances which arenormally included, such as e.g. heparin, heparan sulphate, dermatansulphate and chondroitin sulphate, but also biocompatible fragments,derivatives and conjugates of sulphated glycosaminoglycans.

Among the sulphated glycosaminoglycans, it is well known that e.g.heparin has excellent biocompatibility manifested in anti-coagulatingproperties and capacity of dissolving and preventing thromboses.

The expression “biologically active agent”, as used herein, comprisesany substance(s) which may yield a physiological response whenadministered to a living organism. Thus, said biologically active agentmay also be an active metabolite, drug progenitor or a drug-conjugate,such as a drug-protein (e.g. drug-BSA) conjugate or a drug-spacerconjugate, where the protein or spacer is selected in such a manner thatit will readily adhere to said inner first layer, i.e. to saidbiocompatible carrier. The conjugates may be formed by either covalentbinding or other sufficiently strong intermolecular binding resultingfrom e.g. hydrophobic, hydrogen-binding or hydrophilic interactions.

It should be understood that said biologically active agent may also bea mixture of one or more physiologically active substances, which areused in a particular combination. In this case, the combination ispresent in both said first and second layer, albeit not necessarily inthe same concentration and/or ratio.

The expression “sustained release”, as used herein, means that saidbiocompatible carrier releases no more than 50-90 percent by weight (wt%) of said biologically active agent dissolved or dispersed thereinwithin 7 days after insertion of said medical device into a human oranimal body.

Preferably, said sulphated glycosaminoglycan is selected from heparin,heparan sulphate, dermatan sulphate and chondroitin sulphate, includingbiocompatible fragments, derivatives and conjugates thereof.

In one of the embodiments of the present invention, said sulphatedglycosaminoglycan is heparin or a fragment thereof. It deservesmentioning that heparin is an endogenous sulphated mucopolysaccharidewhich occurrs naturally complex-bound to protein in various mammaliantissues, such as the intestine, liver and lung, and has then an averagemolecular weight (M_(w)) of up to 100 kDa. Commercially availablepreparations of heparin, e.g. as provided by Pharmacia Corp., typicallyhave an M_(w) of between 6 and 20 kDa.

In the preferred embodiment, said sulphated glycosaminoglycan is aheparin conjugate. A conjugate with an organic polymer chain ispreferable. The preparation of heparin conjugates, especially to anorganic polymer chain, is well known in the art and disclosed inter aliain U.S. Pat. No. 5,529,986, the teachings and citations of which areincorporated herein by reference.

Said organic polymer chain is typically selected from a polyaminoacid,preferably polylysine or polyornithine, polyamine, chitosan, polyimine,polyallylamine, a polysaccharide and an aliphatic polymer. Normally, theorganic polymer chain is substantially straight-chained.

It is particularly preferred that said sulphated glycosaminoglycan isconjugated to said organic polymer chain via a coupling (spacer) moiety.The most suitable coupling moiety is provided via a heterobifunctionalcoupling reagent, preferablyN-succinimidyl-3-(2-pyridyldithio)-propionate. (SPDP).

It is most preferred that said sulphated glycosaminoglycan is a heparinconjugate having from about 30 to 500, preferably from about 100 to 250,heparin molecules conjugated to said organic polymer. Said organicpolymer suitably has an average molecular weight of from about 50 to 500kDa, preferably at least about 100 kDa. According to the presentinvention, the most suitable organic polymer is selected frompolylysine, chitosan and polyallylamine, where polylysine is the verymost suitable choice.

For many biologically active agents, a sulphated glycosaminoglycan asthe main and/or only component of said biocompatible carrier willprovide the desired sustained release of a biologically active agentdissolved or dispersed therein. However, some biologically active agentsmay require that the sulphated glycosaminoglycan is admixed with atleast one other polymeric carrier, where the function of the latter isto aid in providing and tuning in the desired (e.g. linear) sustainedrelease profile of said biologically active agent dissolved or dispersedin the resulting admixture. Should the need arise, such admixing isreadily accomplished by a person skilled in the art. See e.g. U.S. Pat.No. 4,767,628 and U.S. Pat. No. 5,869,103, which disclose linearrelease-of a biologically active agent from polymer mixtures.

Thus, in another embodiment, said biocompatible carrier comprises saidsulphated glycosaminoglycan admixed with at least one polymeric carrier,where said polymeric carrier is not a sulphated glycosaminoglycan. Saidpolymeric carrier is preferably biodegradable and selected to aid inproviding the desired sustained release profile of said biologicallyactive agent dissolved or dispersed in said biocompatible carrier. Thefunction of the polymeric carrier may also be to solubilise thesulphated glycosaminoglycan and the biologically active agent and/or toconfer particular adhesive, mechanical or thermal properties.

Said polymeric carrier is preferably selected from poly fatty acidesters, polyurethane and other pharmaceutically acceptable polymericcarriers known in the art. Thus, the following polymers can provide asuitable biocompatible carrier according to the present invention: polyfatty acid esters [e.g. homopolymer (e.g. polylactic acid) of fatty acidor copolymer (e.g. copolymer of lactic acid/glycolic acid, copolymer of2-hydroxybutyric acid/glycolic acid) of two or more fatty acids, amixture of the homopolymer and/or copolymer (e.g. a mixture ofpolylactic acid and copolymer of 2-hydroxybutyric acid/glycolic acid),examples of the fatty acid include α-hydroxycarboxylic acid (e.g.glycolic acid, lactic acid, 2-hydroxy butyric acid, 2-hydroxyvalericacid, 2-hydroxy-3-methyl butyric acid, 2-hydroxycaproic acid,2-hydroxyisocaproic acid, 2-hydroxycaprylic acid), cyclic dimers ofa-hydroxycarboxylic acids (e.g. glycolide, lactide),hydroxydicarboxcylic acid (e.g. malic acid), hydroxytricarboxylic acid(e.g. citric acid)], poly-α-cyanoacrylate, polyalkylene oxalates (e.g.polytrimethylene oxalate, polytetramethylene oxalate), poly orthoesters, poly ortho carbonates and other polycarbonates (e.g.polyethylene carbonate, poly-ethylenepropylene carbonate), polyaminoacids (e.g. poly-γ-benzyl-L-glutamic acid, poly-L-alanine,poly-γ-methyl-L-glutamic acid), polylysine, and the like. Furtherexamples of a suitable biocompatible carrier include polyacrylic acid,polymethacrylic acid, copolymer of acrylic acid and methacrylic acid,polyethyle glycol, silicon polymer, dextran stearate, ethylcellulose,acetylcellulose, maleic anhydride copolymers, ethylene-vinylacetatecopolymer, polyvinyl acetate, polyvinyl alcohol, polyacrylamide and thelike. These polymers may be used alone or in combination. They may beused in the form of a copolymer or mere mixture of these two or morepolymers. They may be in the form of salts thereof. The affinity for theadsorbed molecular coating e.g. film can be enhanced by attachment ofphenylboronic acid moities. For the purposes of the present invention,D-, L- and D,L-isomers are equally suitable.

Preferably, said non-polymeric adjuvant, diluent or carrier is selectedfrom phosphorylcholine and derivatised phosphorylcholine, ionic ornon-ionic surfactants, buffer salts, albumines, liposomes, and contrastmedium; preferably iohexole.

As a non-limiting example of suitable derivatised phosphorylcholines,mention can be made of the compounds disclosed in WO 91/13639 and WO93/22320, the entire teachings of which are incorporated herein byreference.

Moreover, it is preferred that said poly fatty acid ester andpolyurethane has an average molecular weight in the range of from about5 kDa to 200 kDa, preferably from about 10 to 100 kDa.

As an example of a heparin conjugate useful in the present inventionmention can be made of the JOMED Heparin Surface material employed inthe commercially available stent JOSTENT®Flex (manufactured by JOMEDGmbH, Rangendingen, Del.). This heparin conjugate has a M_(w) in theorder of about 1000 kDa.

Preferably, said poly fatty acid ester is polylactic acid (PLA),polyglycolic acid (PGA) or a copolymer of lactic acid and glycolic acid(PLGA). PLGA is particularly preferred, as it is also commerciallyavailable in many varieties (e.g. RG756, RG502H and RG504H provided byBoehringer Ingelheim, Del.). Other preferred polymers arepoly-α-cyanoacrylate and a copolymer of 2-hydroxybutyric acid andglycolic acid.

When PLGA is used, its monomer ratio is preferably about 100/0 to 50/50(w/w). When a copolymer of 2-hydroxybutyric acid and glycolic acid isused, its monomer ratio is preferably about 100/0 to 25/75 (w/w).

The average molecular weight of PLGA and the copolymer of2-hydroxybutyric acid and glycolic acid is preferably about 5 to 30 kDa.When a mixture of a polylactic acid (A) and a copolymer of2-hydroxybutyric acid/glycolic acid (B) is used, the mixture can be usedin a blend (w/w) ratio of about 10/90 to 90/10, preferably about 25/75to 75/25.

The weight-average molecular weight of the polylactic acid (A) ispreferably about 5 to 30 kDa.

The preferred proportion of glycolic acid in the copolymer (B) is about40-70 mol %. The average molecular weight of the copolymer (B) ispreferably about 5 to 25 kDa.

If desired, said biocompatible carrier may additionally contain othersubstances which are generally used in the preparation of pharmaceuticalcompositions. Typical such substances are pharmaceutically acceptableadjuvants, ionic or non-ionic surfactants, adhesives, stabilisers (oftenantioxidants), lubricants and pH regulators. All of these substances arewell known in the art.

Said biologically active agent is preferably present in said inner andouter layer at a concentration of from 0.01 to 99 percent by weight (wt%). Preferably, said inner first layer has a thickness in the range offrom about 0.1 to 1000 μm, preferably at least 0.5 μm.

In the present medical device, said biologically active agent could bean antiinflammatory drug, e.g. COX-1 and −2 inhibitors, prostaglandines,indomethacin, or diclofenac. However, said biologically active agent ispreferably a compound capable of providing release of nitric oxide. Itis further preferred that said compound is a diethylenetriamine/nitricoxide adduct (DETA/NO), sydnonimine or morpholino-sydnonimine. Saidcompound is preferably molsidomine or linsidomine.

One or more agents, i.e. adjuvants, which enhance the amount of NOdelivered to the cells at the site to be treated can also be present.Such agents typically enhance the absorption of NO or its precursor,increase the activity of the NO-releasing compound and/or protect theNO-releasing compound from degradation. Particularly useful such agentsare the vitamins B₆, B₁₂, C and E. Also useful in the practising of thepresent invention are folates, β-carotene, glutathione, coenzyme Q,cysteine, tocopherols, phenolic compounds, thiols, ubiquinones,dexomethasone, heparinoids, Ca²⁺-antagonists, nitrates, protein kinaseinhibitors, anti-thrombin and antiproliferative agents, such ascytostatics, such as metotrexate, mitomycin C, doxyrubicin, somatostatinanalogs, cytoschalasin B, rapamycin and cyclosporins.

In the present medical device, said exterior surface preferably consistsof metal or a biocompatible organic or inorganic polymer. Said metal ispreferably selected from gold, silver, platinum, stainless steel,titanium and biocompatible alloys thereof. Said biocompatible organic orinorganic polymer is preferably selected from fibrin,polytetrafluoroethylene (PTFE), silicone, silicone rubber, nylon andpolyethylene perthalate (Dacron).

Moreover, it is preferred that said medical device is selected fromcatheters, guide wires, balloons, filters, vascular grafts, graftconnectors, tubing, implants, sutures, surgical staples, stentgrafts andstents.

In the most preferred embodiment of the present invention, said medicaldevice is a stent. Particularly preferred are JOSTENT®Flex and JOMEDstentgrafts adapted for coronary use as well as JOSTENT®SelfX,JOSTENT®Peripheral and JOSTENT®Renal for peripheral use.

In addition, the present invention relates to a method for use of saidmedical device as set forth above. More specifically, the presentinvention further relates to a method for promoting tissue healing in ahuman or animal body, wherein said method comprises insertion of amedical device as set forth above into a site where tissue healing isrequired. Even more specifically, the present invention also relates toa method for treatment or prevention of restenosis and disorders relatedthereto in a human or animal body, wherein said method comprisesinsertion of a medical device as set forth above into a site wheretreatment or prevention of restenosis and disorders related thereto isrequired.

Said site is typically an artery, preferably a coronary artery, or apart of the gastrointestinal tract.

The above method is also applicable to the treatment or prevention ofother disorders, such as inflammatory conditions or proliferativedisorders, e.g. cancer diseases. A person skilled in the art willreadily realise how to adapt, if necessary, the practising of thepresent method to the particular disorder and circumstances at hand.

As for the typical dosage of the biologically active agent, it varieswithin a wide range and depends on various factors, such as theparticular requirements of each receiving indvidual and the particularmedical device used. The required dosage range depends on the used agentand circumstance under which it is applied. The dosage is generallywithin the range of 0.001-100 mg/kg body weight, albeit also otherranges may be required under certain circumstances.

The present invention is further illustrated by the followingnon-limiting general experimental part.

The following figures depict the results obtained:

FIG. 1 shows in vitro release of nitric oxide into an aqueous medium, asmeasured by a conventional NO-electrode (pA registered), from glassbeads and silastic tubing coated according to the invention. “Singlelayer coated” refers to a coating consisting of a film of3-morpholino-sydnonimine (SIN-1) only, whereas “double layer coated”refers to a coating consisting of a heparin conjugate carrier layer intowhich SIN-1 has been absorbed, onto which layer a film of SIN-1 ispresent. The term “6” means that six dipping/hardening cycles (seebelow) has been performed for the device in question. The releaseprofile of nitric oxide for 1 h at room temperature is depicted in FIG.1.

FIG. 2 shows the release profile of nitric oxide for the same coatedglass beads and silastic tubing between 24 and 25 hours after continuousimmersion into said aqueous medium.

EXAMPLE Coating of a Stent Having a Smooth Stainless Steel Surface

A JOSTENT®Flex stent made in electropolished Stainless steel 316L iscoated by dipping it at room temperature into an aqueous, preferablypaste-like, solution of heparin conjugate (polylysine conjugate withHeparin A as in Example 1 of U.S. Pat. No. 5,529,986; M_(w)˜3 300 kDa;heparin/polylysine ratio 240:1) as commercially available. A fluidizingsolvent, such as ethanol, or an ethanol/water mixture may also be used.This layer (about 0.5 μm thick; several dipping/hardening cycles may berequired) is sufficiently elastic to, after hardening, retain itsstructural integrity when the stent is subsequently expanded afterinsertion thereof into e.g. an artery. This heparin conjugate coatedstent is then dipped into an aqueous 10⁻⁴ M solution of3-morpholinosydnonimine (SIN-1) for 5 min. A concentration as low as10⁻⁸ M may provide the desired effect, and 1 nM may be effective. Inthis dipping step, the SIN-1 readily diffuses into and is absorbedthroughout the heparin conjugate carrier. The applied coating is thenallowed to harden by conventional means, e.g. by evaporation of thesolvent at room temperature. Normally, both a first and a second layerare formed in this procedure (see the comments to the figures below).The first layer is heparin conjugate carrier incorporating SIN-1,whereas the second layer is a film of SIN-1 present on the heparinconjugate carrier layer.

The above procedure was also performed on glass beads and silastictubes, and the release properties of these devices were investigated invitro. The results are shown in the accompanying figures.

FIG. 1 shows that the immediate (acute) release of nitric oxide from thedouble layer coated devices according to the present invention issufficiently rapid. Indeed, the “6X” coating (about 0.5 μm thick) of thesilastic tubing displays a both rapid and nearly linear release profilefor 1 h. The release of nitric oxide for 1 h is even more rapid from thedevices coated with SIN-1 only (“single layer coated”).

FIG. 2 shows that the single layer coated devices release virtually noor very little nitric oxide after 24 h. However, after this time thedouble layer coated devices according to the present invention stillhave a surprisingly substantial release rate of nitric oxide, and theirrelease rates are now more rapid than those of the single layer coateddevices.

After the hardening, if so desired, the thickness of the second layercan be increased further by dipping at 37° C. the coated stent into anaqueous (or ethanol) solution containing SIN-1 in a concentration rangeof from about 10⁻⁸ M to 10⁻² M, preferably about 10⁻⁴ M. The solvent isthen removed as above. Several such dipping/drying cycles may beperformed for the the second layer as well.

Optionally, the aforementioned aqueous solution or paste of heparinconjugate may also contain dissolved SIN-1. In such a procedure, thesecond layer is applied after the hardening of the resulting heparinconjugate layer into which SIN-1 is incorporated.

The above procedure is readily applied on, or if necessary easilyadapted to, virtually all of the commercially available stents. Typicalsuch stents are

Biodivysion™ (Biocompatibles Ltd., UK), BX high velocity Stainless SteelL316™ (Cordis, Johnson & Johnson Co., USA), NIR Primo Stainless Steel316L™, NIRoyal Stainless Steel 316L™ (coated with a 7 μm layer ofgold-plating), Radius self-expanding Nitinol™ stent (Medinol, Scimed,Boston Scientific Co., USA), S6™ and S7™ (AVE, Metronic, USA), MultilinkDuett™ and Ultra™ (ACS, Guidant S.A., Belgium).

As further non-limiting examples of stents as well as guidewires andangioplasty balloons which are suitable in the practising of the presentinvention, mention can be made of those disclosed in “InterventionalVascular Product Guide”. Ed.: Leon M. B., Mintz G. S., Publ. MartinDunitz, 1999, and “Endovascular Angioplasty material's catalog”, EuropaEdition ISBN 2-913628-06-0, May 2001.

In short, the general potency of the present medical device is basedprimarily on the following principles. Firstly, upon insertion of themedical device into a body, a rapid release of the biologically activeagent is provided. More specifically, the outer second layer willnormally release at least 50% of its biologically active componentwithin 1-24 h after insertion, thereby alleviating acute disorders.Secondly, the inner first layer will thereafter provide a sustainedrelease (vide supra) of its biologically active component, therebyproviding a long-term therapeutic effect as well as a prophylacticeffect. This combined “pulsed” effect of the two layers provides aversatile treatment regimen, as substantiated by the results depicted inFIGS. 1 and 2. The presence of the sulphated glycosaminoglycan confersmaintained biocompatibility as well as prevents thromboses during thetime of treatment.

Although the example above discloses the preparation of a coated stentonly, it should be realised that the procedure is also readily adaptablefor use on virtually any medical device. Hence, the features of thepresent medical device and method for use thereof are applicable withinthe field of medicine in general.

1. Medical device adapted for insertion into a human or animal body,characterised in that its exterior surface is coated with i) an innerfirst layer of a biocompatible carrier comprising a sulphatedglycosaminoglycan and providing sustained release of a biologicallyactive agent dissolved or dispersed therein; ii) an outer second layerconsisting of a film of said biologically active agent applied on saidinner first layer, where said film optionally may contain at least onenon-polymeric adjuvant, diluent or carrier.
 2. Medical device accordingto claim 1, wherein said sulphated glycosaminoglycan is selected fromheparin, heparan sulphate, dermatan sulphate and chondroitin sulphate,including biocompatible fragments, derivatives and conjugates thereof.3. Medical device according to claim 2, wherein said sulphatedglycosaminoglycan is heparin or a fragment thereof.
 4. Medical deviceaccording to claim 2, wherein said sulphated glycosaminoglycan is aheparin conjugate, preferably a conjugate with an organic polymer chain.5. Medical device according to claim 4, wherein said organic polymerchain is selected from a polyaminoacid, preferably polylysine orpolyornithine, polyamine, chitosan, polyimine, polyallylamine, apolysaccharide and an aliphatic polymer.
 6. Medical device according toclaim 5, wherein said organic polymer chain is substantiallystraight-chained.
 7. Medical device according to claim 4, wherein saidsulphated glycosaminoglycan is conjugated to said organic polymer chainvia a coupling moiety.
 8. Medical device according to claim 7, whereinsaid coupling moiety is provided via a heterobifunctional couplingreagent, preferably N-succinimidyl-3-(2-pyridyldithio)-propionate(SPDP).
 9. Medical device according to claim 4, wherein said sulphatedglycosaminoglycan is a heparin conjugate having from about 30 to 500,preferably from about 100 to 250, heparin molecules conjugated to saidorganic polymer.
 10. Medical device according to claim 9, wherein saidorganic polymer has an average molecular weight of from about 50 to 500kDa, preferably at least about 100 kDa.
 11. Medical device according toclaim 10, wherein said organic polymer is selected from polylysine,chitosan and polyallylamine.
 12. Medical device according to claim 1,wherein said biocompatible carrier comprises said sulphatedglycosaminoglycan admixed with at least one polymeric carrier, wheresaid polymeric carrier is not a sulphated glycosaminoglycan.
 13. Medicaldevice according to claim 12, wherein said polymeric carrier is selectedfrom poly fatty acid esters and polyurethane.
 14. Medical deviceaccording to claim 13, wherein said poly fatty acid ester orpolyurethane has an average molecular weight in the range of from about5 kDa to 200 kDa, preferably from about 10 to 100 kDa.
 15. Medicaldevice according to claim 14, wherein said poly fatty acid ester ispolylactic acid (PLA), polyglycolic acid (PGA) or a copolymer of lacticacid and glycolic acid (PLGA).
 16. Medical device according to claim 1,wherein said non-polymeric adjuvant, diluent or carrier is selected fromphosphorylcholine and derivatised phosphorylcholine, ionic or non-ionicsurfactants, buffer salts, albumines, liposomes, and contrast medium;preferably iohexole.
 17. Medical device according to claim 1, whereinsaid biologically active agent is present in said inner and outer layerat a concentration of from 0.01 to 99 percent by weight.
 18. Medicaldevice according to claim 1, wherein said inner first layer has athickness in the range of from about 0.1 to 1000 μm, preferably at least0.5 μm.
 19. Medical device according to claim 1, wherein saidbiologically active agent is a compound capable of providing release ofnitric oxide.
 20. Medical device according to claim 19, wherein saidcompound is a diethylenetriamine/nitric oxide adduct or sydnonimine,preferably molsidomine or linsidomine.
 21. Medical device according toclaim 1, wherein said exterior surface consists of metal or abiocompatible organic or inorganic polymer.
 22. Medical device accordingto claim 21, wherein said metal is selected from gold, silver, platinum,stainless steel, titanium and biocompatible alloys thereof.
 23. Medicaldevice according to claim 21, wherein said biocompatible organic orinorganic polymer is selected from fibrin, polytetrafluoroethylene(PTFE), silicone, silicone rubber, nylon and polyethylene perthalate(Dacron).
 24. Medical device according to claim 1, wherein said medicaldevice is selected from catheters, guide wires, balloons, filters,vascular grafts, graft connectors, tubing, implants, suturs, surgicalstaples, heart valves, stentgrafts and stents.
 25. Medical deviceaccording to claim 24, wherein said medical device is a stent. 26.Method for promoting tissue healing in a human or animal body, whereinsaid method comprises insertion of a medical device according to claim 1into a site where tissue healing is required.
 27. Method for treatmentor prevention of restehosis and disorders related thereto in a human oranimal body, wherein said method comprises insertion of a medical deviceaccording to claim 1 into a site where treatment or prevention ofrestenosis and disorders related thereto is required.
 28. Methodaccording to claim 26, wherein said site is an artery, preferably acoronary artery, or a part of the gastrointestinal tract.